Perigaud, C. et al., Nucleosides and Nucleotides, 11 (2-4), 903-945, (1992) provide a useful overview of the current state of the art relating to the use of nucleosides and/or nucleotides as chemotherapeutic agents (including use as anticancer, antiviral and antibacterial agents). As described in this review article, the term "nucleoside(s)" relates to naturally-occurring nucleosides which are distinguished depending on the base, for example, adenine and guanine (A and G, respectively) have a purine base, whereas cytosine, uracil, thymine and hypoxanthine (C, U, T, and H, respectively) have a pyrimidine base.
Nagasawa, N., et al., J. Org. Chem., 32, 251-252, (1967) describe the production of certain D-ribopyranosyl nucleosides (particularly 9-(2'-Deoxy-.beta.-D-ribopyranosyl)adenosine. Fucik, V., et al., Nucleic Acids Research, Vol. 1, No. 4, (1974), 639-644, describe structural effects of chemical modification upon the affinity of purine nucleosides to cytidine-transport system in Bacillus subtilis using a series of modified derivatives including certain ribopyranosyl nucleosides.
As is well known, sugars found in natural nucleic acids are D-ribose and D-deoxyribose in almost all cases. Much research has been done to investigate the chemical and biological activities of the D-isomers of ribonucleotides and ribonucleosides, however, far less work has been done with the L-isomers. This is primarily due to the fact that the synthesis of the L-isomers is much more difficult, often involving the optical resolution of the D, L-isomers of nucleosides with the aid of microorganisms and enzymes. (See generally, Asai, M., et al., Chem. Pharm. Bull., 15(12), 1863-1870, (1967)). The known activity of D-nucleoside compounds, and the successful commercialization of many of such D-sugar nucleosides (see Perigaud, C., et al., supra, for a discussion of D-nucleoside analogs which have gained commercial acceptance) lead in part to the present work relating to the L-isomers of certain nucleoside analogs.
Perhaps the best known commercial nucleobase analog is 5-fluorouracil (5-FU) the structure of which is shown below: ##STR1## 5-FU is an antimetabolite compound commercially available from Roche and is one of the most commonly used drugs for treating certain types of cancer. The high acceptance of this drug is due in part to its extreme cytotoxic effects. However, this highly toxic compound has a narrow margin of safety and it has many side effects including, for example, GI side effects like nausea, vomiting and diarrhea, leukopenia, thrombocytopenia, alopecia, etc. Additionally, 5-FU is primarily used as an intravenous formulation. Therefore, there is a need for a nucleoside analog which is perhaps as cytotoxic as 5-FU or which is less cytotoxic but more specific than 5-FU, and which preferably can be administered orally.
5-FU is currently dosed at short intervals due to the damage it does to normal cells. The patient is taken off chemotherapy for a time to allow recovery from the cytotoxic effects of the treatment. It is contemplated that if a drug is developed that is less cytotoxic to healthy cells it would no longer be necessary to treat the patient in periodic intervals, which may be associated with the development of multiple drug resistance often exhibited in treated cancer cells. Specifically, as a tumor is being killed the cells that are most resistant to the drug die slower and, therefore, when the treatment is stopped (often because of the toxicity to normal cells), the more resistant tumor cells are left to multiply.
A significant commercial nucleoside analog is azidothymidine (AZT), commercially available as Retrovir from Burroughs Wellcome. AZT, a .beta.-D-deoxy-ribofuranosyl derivative of the formula : ##STR2## is useful as an antiviral agent, particularly against the virus responsible for the Acquired Immune Deficiency Syndrome (AIDS).
This compound, like 5-FU, is associated with a number of undesirable side effects including hematologic toxicity such as granulocytopenia and/or severe anemia.
Without intending to be limited, applicants believe that the L-nucleoside compounds, as claimed in the present invention, may be beneficial over compounds such as 5-FU and AZT since it is believed that L-nucleosides (as claimed) exhibit selective permeability to compromised cells. By compromised cells we mean cells such as cancer cells or other infected cells whether the infection is bacterial, fungal, viral or parasitic. It is believed that the L-nucleosides of the present invention may be transported into or permeate these compromised cells, whereas in normal cells the L-nucleosides would not permeate. (See, for example, Lin, T. S., et al., Abstract entitled "Synthesis and Biological Evaluation of 2', 3'-Dideoxy-L-Pyrimidine Nucleosides as Potential Antiviral Agents against HIV and HBV", published J. Med. Chem., (1994), 37, 798-803; and Spadari, S., et al., J. Med. Chem., (1992), 35 4214-4220.) Therefore, to the extent these L-nucleosides are selective for compromised cells, they are less harmful to normal cells than compounds like 5-FU.
In addition to this concept of selective permeability, in viral-infected cells where therapeutic compounds often have an inhibitory mechanism related to the RNA of the cell, it is contemplated that the enzymes of such viral-infected cells may be less specific than in a normal cell and, therefore, if you can permeate the cell with an L-nucleoside, a more primitive enzyme (such as an organic phosphorylases, kinase or thymidylate synthase) may recognize the compound in such a way as to cause inhibition.
The present invention, therefore, relates to a novel group of such L-pyranosyl nucleosides which have interesting activity as anticancer, antiviral, antiparasitic, antifungal and/or antimicrobial agents. These compounds are generally water soluble, which suggests that oral deliver may be achieved. This would be specifically advantageous versus anticancer compounds such as 5-FU. And the activity of these compounds may be more selective for compromised cells as compared to normal cells, suggesting that compounds of this invention will cause fewer side effects than similar compounds such as 5-FU.